In recent years, the increase of patients with elderly dementia is becoming a great social problem of the aging population. The main cause of elderly dementia is Alzheimer's disease (hereinafter sometimes to be abbreviated as “AD”). Based on genetic abnormality in familial Alzheimer's disease (FAD), the mechanisms of the formation of senile plaque and neurofibrillary tangle and the like have been increasingly revealed.
The major constituent of senile plaque is a highly aggregatable peptide called Aβ consisting of about 40 amino acid residues, which is produced by cleavage of a part of amyloid precursor protein (APP) consisting of 770 amino acids. Since both the responsible gene and susceptibility gene identified in FAD promote production and accumulation of Aβ, the accumulation of Aβ is believed to cause the onset of AD, and intensive studies have been performed to confirm this belief. Aβ has some molecular species having different lengths due to cleavage site (γ-secretase cleavage site) differences at its C terminal. Among these molecular species, Aβ40 consisting of 40 amino acid residues and Aβ42 consisting of 42 amino acid residues are important. Aβ42 is more likely to aggregate, and the pathogenicity thereof is higher than Aβ40.
In FAD with the Swedish mutation, it is known that there are two mutations at 2 amino acid residues just before the Aβ region in APP gene (Nat. Genet., 1(5): 345-7 (1992)), and that the total amount of Aβ in the brain is remarkably higher than that in normal individuals. Moreover, in vitro research involving mutations artificially introduced to each amino acid residue just after the γ-secretase cleavage site indicated that a substitution of the 716th isoleucine (Ile) with phenylalanine (Phe) in APP (I716F) increased the Aβ42/Aβ40 ratio by about 30-fold (Proc. Natl. Acad. Sci. USA, 96: 3053-8 (1999)). However, the results of any research involving FAD with such mutations have not been reported.
To reveal the pathology of the disease and to develop a therapeutic drug for the disease, it is necessary to develop a model animal of the disease. Tg2576 mouse, which is currently used worldwide as a model mouse of AD, is an APP transgenic (Tg) mouse brain over-expressing human APP gene with the Swedish mutation, and can reproduce the development of senile plaque and AD pathology, such as learning and memory disorders (Science, 274: 99-102 (1996)). However, subsequent investigations have revealed that the death of neuronal cells and loss of synapses are not observed in the hippocampus of this mouse, and that the reproduction of neurofibrillary tangle and neurodegeneration is insufficient. APP Tg mouse other than Tg2576 mouse (see, e.g. Nature, 373: 523-7 (1995), and Nature, 395: 755-6 (1998)) and a model mouse of AD wherein another gene was modified (see, e.g., Nature, 383: 710-3 (1996), and Neuron, 17: 181-90 (1996)) only reproduce a part of the pathology in the brain of an AD patient, and fail to reproduce all of the series of pathologies occurring in human.